title: Role of 20-HETE, TRPC channels, and BKCa in dysregulation of pressure-induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice.
abstract: Hypertension in the elderly substantially increases the risk of stroke and vascular cognitive impairment in part due to an impaired functional adaptation of aged cerebral arteries to high blood pressure. To elucidate the mechanisms underlying impaired autoregulatory protection in aging, hypertension was induced in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic infusion of angiotensin II and pressure-induced changes in smooth muscle cell (SMC) intracellular Ca(2+) concentration ([Ca(2+)]i) and myogenic constriction of middle cerebral arteries (MCA) were assessed. In MCAs from young hypertensive mice, pressure-induced increases in vascular SMC [Ca(2+)]i and myogenic tone were increased, and these adaptive responses were inhibited by the cytochrome P-450 ω-hydroxylase inhibitor HET0016 and the transient receptor potential (TRP) channel blocker SKF96365. Administration of 20- hydroxyeicosatetraenoic acid (HETE) increased SMC [Ca(2+)]i and constricted MCAs, and these responses were inhibited by SKF96365. MCAs from aged hypertensive mice did not show adaptive increases in pressure-induced calcium signal and myogenic tone and responses to HET0016 and SKF96365 were blunted. Inhibition of large-conductance Ca(2+)-activated K(+) (BK) channels by iberiotoxin enhanced SMC [Ca(2+)]i and myogenic constriction in MCAs of young normotensive animals, whereas it was without effect in MCAs of young hypertensive mice. Iberiotoxin did not restore myogenic adaptation in MCAs of aged hypertensive mice. Thus functional maladaptation of aged cerebral arteries to hypertension is due to the dysregulation of pressure-induced 20-HETE and TRP channel-mediated SMC calcium signaling, whereas overactivation of BK channels is unlikely to play a role in this phenomenon.
authors.affiliation: Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma;
authors.forename: Peter
authors.initials: P
authors.lastname: Toth
authors.forename: Anna
authors.initials: A
authors.lastname: Csiszar
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Tucsek
authors.forename: Danuta
authors.initials: D
authors.lastname: Sosnowska
authors.forename: Tripti
authors.initials: T
authors.lastname: Gautam
authors.forename: Akos
authors.initials: A
authors.lastname: Koller
authors.forename: Michal Laniado
authors.initials: ML
authors.lastname: Schwartzman
authors.forename: William E
authors.initials: WE
authors.lastname: Sonntag
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
mesh_terms: D000375:Aging / Q000502:physiology; D000804:Angiotensin II; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D050052:TRPC Cation Channels / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: C530995:BKCa protein, mouse; D006893:Hydroxyeicosatetraenoic Acids; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D050052:TRPC Cation Channels; D000804:Angiotensin II; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D002118:Calcium
keywords: 20-hydroxyeicosatetraenoic acid; autoregulation; canonical transient receptor potential; cerebral blood flow; large-conductance Ca2+-activated K+ channels; potassium channels